An important goal of this proposal is to link the integrated computational modeling of genetic and physiological systems to experimental studies in defined strains. Throughout Projects 1-4, the use of already recently developed models and the generation of several new animal models are proposed. We will use our expertise in rat breeding and high throughput genotyping, rat germline transgenesis, gene knockout, as well as newly developed approaches for gene knockin, as the various projects dictate and as new predictions and testable hypotheses emerge. The selection of the models will be based on several criteria. First and most importantly, is the strain likely to give phenotype information that could be modeled or predicted by the simulation toolsets? Second, is disruption of the gene likely to lead to a viable animal model? We will determine whether a mouse KO model has been successfully produced. Thirdly, is the strain likely to be a valuable model to the research community? In Project 5, the validated simulation tool sets will be combined to understand integrated systems function and different model strains will be likewise combined through breeding to test simulations of the integrated toolsets.